Rituxan for treatment of idiopathic factor VIII inhibitors

1. Rituxan for treatment of idiopathic factor VIII inhibitors Timothy S. Fenske, M.D. Heme/Onc Grand Rounds June 13, 2003

2. Outline Review clinical features and diagnosis of idiopathic factor VIII inhibitors Standard treatments Immediate actions to obtaining hemostasis Elimination of inhibitor Wash U experience using Rituxan Published reports using Rituxan

3. Clinical features Affects 1 patient per 1 million people per year Associated with other disease in about 50% of cases Autoimmune (12%): RA, SLE, GCA, UC, dermatomyositis, Sjogren�s, cryoglobulinemia Malignancy (10-15%): ALL, CLL, HCL, lymphoma, lung, colon, kidney, prostate, ovary Pregnancy (3rd trimester) or post-partum (10%) Drug reaction (3-6%): PCN, ampicillin, phenytoin, sulfa drugs, quinolones Skin disorders (2-5%): psoriasis, pemphigus, erythema multiforme, others

4. Clinical features Bleeding in some cases, first noted after a surgical procedure Large hematomas extensive ecchymoses severe mucosal bleeding epistaxis, GI bleeding, gross hematuria Spontaneous hemarthroses, which are common in hereditary factor VIII deficiency, are unusual

5. Clinical features Bleeding is often severe In published series, 75-87% with �major� bleeding (requiring transfusion) 14-22% mortality from complications directly or indirectly related to the inhibitor

6. Diagnosis Common scenario: sudden presence of large hematomas or extensive ecchymoses in an elderly pt without significant trauma or known bleeding disorder Prolonged aPTT normal PT / INR Failure of prolonged aPTT to correct with 50:50 mix

7. Diagnosis - mixing study Mix patient plasma 50:50 with pooled normal plasma check aPTT immediately after mix check aPTT after 1 hour incubation at 37 C This is necessary to detect some factor VIII inhibitors with slow reaction kinetics Prolonged aPTT after incubation establishes whether an inhibitor is present but does not identify the inhibitor specificity.

8. Diagnosis - mixing studies Next step is to add a source of phospholipid to the mixed plasma. Correction of the aPTT suggests the presence of antiphospholipid antibodies. If the aPTT does not correct, check fac VIII activity If factor VIII activity is low, Bethesda assay is then performed to quantitate the strength of the inhibitor serial dilutions of patient plasma are incubated with pooled normal plasma at 37�C for two hours The reciprocal dilution of patient plasma that results in 50 percent factor VIII activity is defined as one Bethesda unit (BU) establishes the diagnosis of a factor VIII inhibitor and quantifies the antibody titer

9. Biochemical properties Usually heterdimers of polyclonal origin Often IgG4 kappa Can be against various epitopes Can be completely or partially neutralizing In lymphoproliferative disorders or myeloma, monoclonal IgA or IgM inhibitors have been described

10. Treatment Control bleeding: initial Rx based upon the severity of bleeding and the titer of the inhibitor pRBC transfusions Avoid IM injections, punctures, etc Avoid aspirin, NSAIDs, clopidogrel, etc desmopressin (dDAVP) Increases factor VIII and vWF levels May help achieve hemostasis in mild cases human factor VIII concentrates: If BU <5 porcine factor VIII concentrate Low chance of cross-reactivity except for hemophila A pts Overall approx 80% response rate Goal is to get Fac VIII activity >30%

11. Treatment Activated prothrombin complex concentrates (FEIBA: factor eight inhibitor bypass activity) Contain varying amounts of vit K dependent factor (II, VII, IX, X), manipulated to get partial activation of factors VII, IX and X. 65-95% effective Thrombosis risk (VTE, MI, DIC) Dose 50-100 U/kg. Max 200 U/kg/day No good lab parameter to follow � follow clinicially Avoid concurrent antifibrinolytic Rx Recombinant human factor VIIa (NovoSeven) 75-90% effective for serious bleeding in general Dose 90 ug/kg initial dose, then 45 ug/kg q4h maint until no bleeding Very expensive Antifibrinolytic Rx (Amicar): anecdotal data